Metabolic syndrome is characterized by a group of factors, such as increased waist circumference, dyslipidemia (low HDL, high LDL), increased blood pressure and increased insulin resistance or glucose intolerance. It is estimated that 50 million people in the US suffer from metabolic syndrome. People with metabolic syndrome are at higher risk for developing cardiovascular disease and type-2 diabetes (T2D). We have identified the enzyme Nicotinamide N-methyltransferase (NNMT) as a novel regulator of glucose and lipid homeostasis. NNMT methylates nicotinamide. Both compounds nicotinamide and N1-methylnicotinamide have biological activity. Nicotinamide is a potent inhibitor of sirtuins, recently recognized important metabolic regulators in the liver and other tissues. N1-methylnicotinamide increases the production of prostaglandins, which among other actions have profound effects on the function of adipose tissue. We hypothesize that NNMT activity regulates hepatic and fat glucose and lipid metabolism through sirtuin-dependent and independent pathways. The aims are: 1) To assess the in vivo role of NNMT in glucose and lipid homeostasis. We will investigate the effects of NNMT overexpression or knockdown on glucose, lipid and cholesterol metabolism in mouse models of obesity and diabetes. 2) To investigate the mechanisms by which NNMT regulates pathways of lipid and cholesterol metabolism in vitro. We will use primary hepatocytes with targeted NNMT overexpression or knockdown to directly assess the activity of pathways in lipid and cholesterol metabolism. We will assess the activity of the master transcriptional regulators LXRa and PPARa to provide a mechanistic explanation for the observed changes. 3) To evaluate the role of NNMT in adipogenesis of 3T3-L1 cells. We will investigate the pathways regulated by NNMT and nicotinamide during adipogenesis to provide evidence that vitamin B3 plays an essential role during the development of adipose tissue. This proposal has direct relevance to the NIDDK mission and will establish NNMT as a potential new candidate gene for the treatment of the metabolic syndrome. PUBLIC HEALTH RELEVANCE: Type-2 diabetes and fatty liver disease have become a major public health threat. We are discovering novel factors and pathways regulating glucose and lipid metabolism. The knowledge gained from this research might open new therapeutic options for these diseases.